title: Allosteric modulators of glycoprotein hormone receptors: discovery and therapeutic potential.
abstract: The glycoprotein hormones, luteinizing hormone, follicle-stimulating hormone and thyroid stimulating hormone, are important regulators of reproductive and metabolic processes. However, because of the nature of their ligand-receptor interactions that contain multiple contact sites, classical small molecule drug discovery strategies have not been successful. However, recent advances in screening and combinatorial chemistry strategies have identified chemical series that act allosterically as positive, negative or mixed modulators of the glycoprotein hormone receptors. This review will discuss the discovery and highlight the currently known series of allosteric modulators to this therapeutically important family of G-protein coupled receptors. Lastly, we will present potential mechanisms whereby the different series could modulate receptor function in the context of currently held theory and known structure of G protein-coupled receptors.
authors.affiliation: Department of Metabolic and Cardiovascular Drug Discovery, Research and Development, Bristol-Myers Squibb Co, 311 Pennington Rocky-Hill Rd, Mail Stop 21-1.08, Pennington, NJ 08534, USA. brian.arey@bms.com
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Arey
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015195:Drug Design; D020555:GTP-Binding Protein Regulators / Q000138:chemical synthesis / Q000627:therapeutic use; D006023:Glycoproteins / Q000378:metabolism*; D006727:Hormone Antagonists / Q000138:chemical synthesis / Q000627:therapeutic use*; D006728:Hormones / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D018000:Receptors, Peptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000032:analysis / Q000627:therapeutic use
chemical_list: D020555:GTP-Binding Protein Regulators; D006023:Glycoproteins; D006727:Hormone Antagonists; D006728:Hormones; D018000:Receptors, Peptide; D054852:Small Molecule Libraries